Sam Keaveney1, Ross Maxwell1, Maelene Lohézic2, Rolf Schulte3, Ralph Noeske4, and Andrew Blamire1
1Newcastle Magnetic Resonance Centre, Newcastle University, Newcastle upon Tyne, United Kingdom, 2GE Healthcare, Manchester, United Kingdom, 3GE Healthcare, Munich, Germany, 4GE Healthcare, Berlin, Germany
Synopsis
Mitochondrial function in the
brain can be measured with magnetisation transfer 31P-MRS. The
conventional approach to magnetisation transfer incurs lengthy acquisition times, limiting the available spatial
information. An accelerated approach, based on kinetic modelling, allows the
technique to be extended to a multi-voxel implementation. Both approaches were
applied in a group of healthy subjects to measure the rate of the creatine
kinase reaction. There was good agreement between the reaction rates measured
with the two methods in equivalently positioned voxels, validating the use of
the accelerated approach to provide greater spatial resolution in future
patient studies.
Introduction
A deficit in mitochondrial function
has been implicated in neurodegeneration and in healthy ageing1.
Regional posterior cortical hypometabolism, observed with FDG-PET, is a
characteristic feature of Alzheimer’s disease and regions of hypometabolism may
reflect mitochondrial dysfunction. The rate of mitochondrial ATP production
through the creatine kinase (CK) reaction, k1, can be measured with
magnetisation transfer (MT) 31P-MRS by saturating γ-ATP and
measuring the resulting reduction in PCr signal. In this work, two methods for
measuring k1 with 31P-MT were applied and compared in
healthy subjects.
The conventional approach to MT
is the progressive saturation transfer (PST) method2, in which PCr
signal reduction is measured with respect to the duration of γ-ATP
saturation (tsat). The PST method is restricted to single voxel
localisation, or reliant on intrinsic surface coil localisation, because of the
lengthy acquisition time. A faster MT approach is required in order to extend
the technique to a multi-voxel implementation. When combined with simultaneous
FDG-PET, this potentially facilitates the comparison of mitochondrial function in
regions of normal and abnormal glucose metabolism. The nominal T1 (T1nom)
method3 is an accelerated approach that uses kinetic modelling to
estimate the T1nom of PCr under partially relaxed conditions. This
is used to calculate k1 with just two measurements: PCr signal with
and without saturation of γ-ATP. Before it can be applied in patient groups, the T1nom
approach must first be validated through comparison with the more established
PST method. Methods
Both approaches were applied in a
group of four healthy volunteers, mean age = 30.5 ± 3.6 years, on a 3 T scanner
(Signa PET/MR, GE Healthcare, Waukesha, WI) with a dual-tuned 31P-1H
head coil (Rapid Biomedical, Rimpar, Germany). Frequency-selective saturation
was achieved with a BISTRO saturation scheme4. The PST method was
applied with ISIS single voxel localisation5, voxel volume = 64 cm3,
TR = 10 s, and NSA = 3. The voxel was positioned in the posterior parietal
cortex. Spectra were acquired with saturation applied at the frequency of γ-ATP
with six tsat values ranging from 0.0 to 4.9 s. The integral of the
PCr peak was quantified using jMRUI and AMARES. The ratio of PCr signal with
saturation (S(tsat)) to PCr signal without saturation (S0)
was fit against tsat to a mono-exponential decay2 (Eq. 1)
in Matlab in order to calculate k1.
$$ \text{Eq.1:} \frac{S(t_{sat})}{S_{0}}=\frac{k_{1}}{(k_{1}+T_{1,PCr}^{-1})}exp(-(k_{1}+T_{1,PCr}^{-1})t_{sat})+\frac{1}{(k_{1} T_{1,PCr}+1)}$$
The
T1nom method was implemented with an 8 x 8 2D CSI matrix, axial slice
thickness = 4 cm, nominal voxel volume = 64 cm3, TR = 3 s, and FA =
72°. Spectra were acquired with and without saturation of γ-ATP,
with tsat = 1.7 s. Variable k-space weighting was used to maximise SNR
while maintaining similar total acquisition time to the PST method. The
Bloch-McConnell equations were used to simulate the relationship between S0
/ S(tsat= 1.7 s) and k1. The gradient and intercept of the
line obtained by linear regression of this relationship are estimates of T1nom
and the constant β respectively3. These simulated values were then used along with the measured ratio S0
/ S(tsat= 1.7 s) to calculate k1 for each voxel using the
relationship shown in Eq. 2.
$$\text{Eq.2:} \frac{S_{0}}{S(t_{sat} = 1.7 s)}=k_{1}T_{1nom}+β$$
Total acquisition time was 28 min
0 s and 26 min 6 s for the PST and T1nom methods respectively. Results
Representative in vivo spectra collected using the PST
and T1nom method are shown in Fig. 1 and Fig. 2 respectively. For
the PST method, PCr signal ratio was fit to Eq. 1, as shown in Fig. 3, calculating
a mean k1 of 0.225 s-1
(std. = 0.016 s-1). For the T1nom method, the simulated
correction parameters were β = 0.97 ± 0.08 and T1nom =
2.46 s ± 0.27 s. SNR was acceptable (>10) in nine voxels of the CSI
matrix. Across those nine voxels, mean k1
was 0.211 s-1 (std. = 0.059 s-1). In the voxel positioned
approximately equivalently to the voxel in the PST approach, mean k1
was 0.218 s-1 (std. = 0.006 s-1). For k1
measured in the equivalent voxel, Bland-Altman analysis determined a mean bias
of + 0.007 s-1 (std. = 0.016 s-1) for the PST method
(Fig. 4). A Wilcoxon signed-ranks test indicated that there was not a
statistically significant difference between values measured with the two
approaches (Z = -0.730, p = 0.625). Discussion
Both approaches measured CK rates
that are in reasonable agreement with values reported in the literature for healthy
subjects6. For equivalently positioned voxels in the posterior
parietal cortex, there was not a statistically significant difference between
the reaction rates measured with each method. This result indicates that the T1nom
method can be used to measure k1 values that are in good agreement
with those measured using the PST approach.Conclusion
Cerebral mitochondrial function
in healthy subjects can be measured using the accelerated T1nom
method. This makes it possible to compare measurements in different regions of
the brain within a similar total scan time as the single voxel PST
implementation. The T1nom method can be combined with simultaneous
FDG-PET and used to investigate the relationship between mitochondrial function
and glucose metabolism across the brain in patients with
neurodegeneration. Acknowledgements
Sam Keaveney's PhD studentship is funded by GE Healthcare.References
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